ANALYTICAL METHOD VALIDATION

AND INSTRUMENT PERFORMANCE

VERIFICATION
ANALYTICAL METHOD VALIDATION
AND INSTRUMENT PERFORMANCE
VERIFICATION

Edited by

CHUNG CHOW CHAN

Eli Lilly Canada, Inc.

HERMAN LAM
GlaxoSmithKline Canada, Inc.

Y. C. LEE
Patheon YM, Inc.

XUE-MING ZHANG
Novex Pharma

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright  2004 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data:

Analytical method validation and instrument performance verification /

Chung Chow Chan . . . [et al.].
p. ; cm.
Includes bibliographical references and index.
ISBN 0-471-25953-5 (cloth : alk. paper)
1. Drugs—Analysis—Methodology—Evaluation. 2.
Laboratories—Equipment and supplies—Evaluation. 3.
Laboratories—Instruments—Evaluation.
[DNLM: 1. Chemistry, Pharmaceutical—instrumentation. 2. Chemistry,
Pharmaceutical—methods. 3. Clinical Laboratory Techniques—standards.
4. Technology, Pharmaceutical—methods. QV 744 A532 2004] I. Chan,
Chung Chow.
RS189.A568 2004
610
.28—dc21
2003014141

Printed in the United States of America.

10 9 8 7 6 5 4 3 2 1
CONTENTS

Contributors vii
Preface ix

1 Overview of Pharmaceutical Product Development and Its

Associated Quality System 1
Chung Chow Chan and Eric Jensen

2 Potency Method Validation 11

Chung Chow Chan

3 Method Validation for HPLC Analysis of Related Substances

in Pharmaceutical Drug Products 27
Y. C. Lee

4 Dissolution Method Validation 51

Chung Chow Chan, Neil Pearson, Anna Rebelo-Cameirao, and Y. C. Lee

5 Development and Validation of Automated Methods 67

Chantal Incledon and Herman Lam

6 Analysis of Pharmaceutical Inactive Ingredients 85

Xue-Ming Zhang

7 Validation Study of JP Heavy Metal Limit Test 95

Yoshiki Nishiyama
v
vi CONTENTS

8 Bioanalytical Method Validation 105

Fabio Garofolo

9 Procurement, Qualification, and Calibration of Laboratory

Instruments: An Overview 139
Herman Lam

10 Performance Verification of UV–Vis Spectrophotometers 153

Herman Lam

11 Performance Verification of HPLC 173

Herman Lam

12 Operational Qualification of a Capillary Electrophoresis

Instrument 187
Nicole E. Baryla

13 LC-MS Instrument Calibration 197

Fabio Garofolo

14 Karl Fisher Apparatus and Its Performance Verification 221

Rick Jairam, Robert Metcalfe, and Yu-Hong Tse

15 The pH Meter and Its Performance Verification 229

Yu-Hong Tse, Rick Jairam, and Robert Metcalfe

16 Qualification of Environmental Chambers 243

Gilman Wong and Herman Lam

17 Equipment Qualification and Computer System Validation 255

Ludwig Huber

18 Validation of Excel Spreadsheet 277

Heiko Brunner

Index 299
CONTRIBUTORS

Nicole E. Baryla, Ph.D., Eli Lilly Canada, Inc., 3650 Danforth Avenue, Toronto,
Ontario M1N 2E8, Canada
Heiko Brunner, Ph.D., Lilly Forschung GmbH, Essener Strasse 93, D-22419
Hamburg, Germany
Chung Chow Chan, Ph.D., Eli Lilly Canada, Inc., 3650 Danforth Avenue,
Toronto, Ontario M1N 2E8, Canada
Fabio Garofolo, Ph.D., Vicuron Pharmaceuticals, Inc., via R. Lepetit 34,
I-21040 Gerenzano, Italy
Ludwig Huber, Ph.D., Agilent Technologies, Hewlett-Packard Strasse 8, 76337
Waldbronn, Germany
Chantal Incledon, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,
Mississauga, Ontario L5N 6L4, Canada
Rick Jairam, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,
Mississauga, Ontario L5N 6L4, Canada
Eric Jensen, Ph.D., Eli Lilly & Company, Indianapolis, IN
Herman Lam, Ph.D., GlaxoSmithKline Canada, Inc., 7333 Mississauga
Road North, Mississauga, Ontario L5N 6L4, Canada
Y.C. Lee, Ph.D., Patheon YM, Inc., 865 York Mills Road, Toronto, Ontario
M3B 1Y5, Canada
Robert Metcalfe, Ph.D., GlaxoSmithKline Canada, Inc., 7333 Mississauga
Road North, Mississauga, Ontario L5N 6L4, Canada

vii
viii CONTRIBUTORS

Yoshiki Nishiyama, Eli Lilly Japan KK, 4-3-3 Takatsukadai, Nishi-ku, Kobe
651-2271, Japan
Neil Pearson, Eli Lilly Canada, Inc., 3650 Danforth Avenue, Toronto, Ontario
M1N 2E8, Canada
Anna Rebelo-Cameirao, Eli Lilly Canada, Inc., 3650 Danforth Avenue,
Toronto, Ontario M1N 2E8, Canada
Yu-Hong Tse, Ph.D., GlaxoSmithKline Canada, Inc., 7333 Mississauga
Road North, Mississauga, Ontario L5N 6L4, Canada
Gilman Wong, GlaxoSmithKline Canada, Inc., 7333 Mississauga Road North,
Mississauga, Ontario L5N 6L4, Canada
Xue-Ming Zhang, Ph.D., Novex Pharma, 380 Elgin Mills Road East, Richmond
Hill, Ontario L4C 5H2, Canada
PREFACE

For pharmaceutical manufacturers to achieve commercial production of safe and

effective medications requires the generation of a vast amount of reliable data
during the development of each product. To ensure that reliable data are generated
in compliance with current Good Manufacturing Practices (cGMPs), all analyt-
ical activities involved in the process need to follow Good Analytical Practices
(GAPs). GAPs can be considered as the culmination of a three-pronged approach
to data generation and management: method validation, calibrated instrument, and
training. The requirement for the generation of reliable data is very clearly repre-
sented in the front cover design, where the three strong pillars represent method
validation, calibrated instrument, and training, respectively.
This book is designed to cover two of the three pillars of data generation. The
chapters are written with a unique practical approach to method validation and
instrument performance verification. Each chapter begins with general require-
ments and is followed by the strategies and steps taken to perform these activities.
The chapter ends with the author sharing important practical problems and their
solutions with the reader. I encourage you to share your experience with us, too.
If you have observations or problem solutions, please do not hesitate to email
them to me at chung chow chan@cvg.ca. With the support of the Calibration &
Validation Group (CVG) in Canada, I have set up a technical solution-sharing
page at the Web site www.cvg.ca. The third pillar, training, is best left to indi-
vidual organizations, as it will be individualized according to each organization’s
strategy and culture.
The method validation section of this book discusses and provides guidance for
the validation of common and not-so-common analytical methods that are used to
support development and for product release. Chapter 1 gives an overview of the
activities from the discovery of new molecules to the launch of new products in
ix
x PREFACE

the pharmaceutical industry. It also provides an insight into quality systems that
need to be built into the fundamental activities of the discovery and development
processes. Chapters 2 to 5 provide guidance and share practical information for
validation of common analytical methods (e.g., potency, related substances, and
dissolution testing). Method validation for pharmaceutical excipients, heavy met-
als, and bioanalysis are discussed in Chapters 6 to 8.
The instrument performance verification section of the book provides unbiased
information on the principles involved in verifying the performance of instru-
ments that are used for the generation of reliable data in compliance with cGMPs.
The reader is given different approaches to the successful verification of instru-
ment performance. The choice of which approach to implement is left to the
reader based on the needs of the laboratory. Chapters 9 to 15 provide infor-
mation on common analytical instruments used in the development laboratory
(e.g., HPLC, UV–Vis spectrophotometers, and pH meters). Chapter 13 provides
a detailed discussion of the LC-MS system, which is fast becoming a standard
analytical laboratory instrument. Since a great portion of analytical data from the
drug development process comes from stability studies, Chapter 16 is included
to provide guidance to ensure proper environmental chamber qualification.
Computers have become a central part of the analytical laboratory. Therefore,
we have dedicated the last two chapters to an introduction to this field of computer
system and software validation. Chapter 17 guides quality assurance managers,
lab managers, information technology personnel, and users of equipment, hard-
ware, and software through the entire qualification and validation process, from
writing specifications and vendor qualification to installation and to both initial
and ongoing operations. Chapter 18 is an in-depth discussion of the approaches
to validation of Excel spreadsheets, one of the most commonly used computer
programs for automatic or semiautomatic calculation and visualization of data.
The authors of this book come from a broad cultural and geographical base of
pharmaceutical companies, vendors and contract manufacturers and offer a broad
perspective to the topics. I want to thank all the authors, co-editors, reviewers,
and the management teams of Eli Lilly & Company, GlaxoSmithKline Canada,
Inc., Patheon Canada, Inc., Novex Pharma, and Agilent Technologies who have
contributed to the preparation of this book. In addition, I want to acknowledge
Herman Lam for the design of the front cover, which clearly depicts the cGMP
requirements for data generation.

CHUNG CHOW CHAN, PH.D.